Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention

The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstream HER2 has been associated with breast cancer initiating cells (CICs) and in some cases resistance to treatment. The anti-diabetes drug metformin can suppress the growth of breast CICs and herceptin-resistant HER2+ cells. This review will discuss the importance of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but will also include relevant examples from other cancer types. The targeting of this pathway will be discussed as well as clinical trials with novel small molecule inhibitors. The targeting of the hormone receptor, HER2 and EGFR1 in breast cancer will be reviewed in association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway.USAMRMC {[}BC022276]; Intramural RECDA Award; Italian Association for Cancer Research (AIRC); MIUR-PRIN; Italian MIUR-FIRB Accordi di Programma; Italian ``Ministero dell'Istruzione, dell'Universita e della Ricerca (Ministry for Education, Universities and Research) - FIRB-MERIT {[}RBNE08YYBM]; Italian Ministry of Economy and Finance; Italian Ministry of Health, Ricerca Finalizzata Stemness; MIUR FIRB {[}RBAP11ZJFA\_001]; CRO; Italian Association for Cancer Research, (AIRC) (RM PI); Italian Association for Cancer Research, (AIRC) {[}MCO10016]; Italian Ministry of Health; Regione Friuli Venezia-Giuli

Validation of a microarray-based gene expression test for tumors with uncertain origins using formalin-fixed paraffin-embedded (FFPE) specimens

e22015 Background: Microarray-based gene expression has been validated as an aid in the diagnosis of tumors with uncertain origins when the specimen is frozen tissue. Microarray use has been largely limited to RNA derived from frozen specimens. This study evaluated performance of a microarray-based test in identifying the tumor type in FFPE specimens. Methods: ZFFPE human tumor specimens (n=405) representing the 15 tissue of origin sites on the Pathwork® Tissue of Origin Test panel were blinded and evenly distributed between two independent processing labs. All specimens consisted of a 10-μm-paraffin curl containing at least 60% viable tumor and were either metastatic or poorly differentiated primaries. Each specimen was processed through RNA extraction, amplification, labeling, hybridization to a Pathchip® microarray, and was scanned to generate a qualified data file. A pre-specified classification algorithm utilizing more than 1500 genes was applied to each data file to yield Similarity Scores corresponding to the 15 tissues on the test panel. Results were then unblinded and compared to the available diagnoses. Results: Of the 405 specimens, 352 yielded qualified data files (87%). Based on the top Similarity Score, the overall agreement with available diagnoses was 89% (95% CI, 85%-92%) and for each specimen an average of 12 out of 15 tissues could be ruled out with &gt; 99% probability. Results for all tissue types were highly informative with diagnostic odds ratios ranging from 178 to 28509. Performance was similar for metastatic (n=150; 91% agreement) and poorly differentiated primary specimens (n=202; 87% agreement). Conclusions: The large size of this study allows an accurate estimate of the confidence of test predictions for both ruling in and ruling out tissues as likely sites of primary origin. The Pathwork Tissue of Origin Test makes the potential benefits of microarray-based gene expression tests for tumors with uncertain origins available for use with the most common type of histology specimen, FFPE. [Table: see text] </jats:p

Neuroepithelial Cysts of the Posterior Fossa: Pathogenesis and Report of Two Cases

Abstract We present two cases of simple neuroepithelial cyst-one at the cerebellopontine angle and the other in the pontine brain stem-in which a basement membrane was detected. The pathogenesis of these cysts, their diagnosis using computed tomography-metrizamide cisternography and nuclear magnetic resonance imaging, and their surgical treatment by fenestration and drainage are discussed.</jats:p